RESEARCH PROJECT III: Histone H3K9 Methylation and Trophoblast Lineage Developmen

项目概要/摘要（研究项目III） 怀孕的建立需要获得胚胎和女性的关键能力 生殖道胚胎能力的核心是滋养层细胞系的发育， 胚胎发生过程中的初始分化事件。滋养层细胞位于胚胎-子宫 界面，并从根本上有助于胚胎在女性生殖系统中的生长和存活。 道。这些重要的任务是通过滋养层干细胞（TS）的适当扩增来完成的， 其专业化的积累促进滋养层对子宫环境的修饰。中断 滋养层细胞谱系发育与着床失败、复发性妊娠丢失和 一系列影响胎盘形成、胎儿生长和产后发育的疾病。因此，必须 了解TS细胞更新和分化调节的分子机制。 转录和表观遗传调节因子控制这些基本过程，这些过程在整个过程中是保守的。 利用血绒膜胎座式的种。我们已经证明了一组明确的组蛋白 TS细胞更新和分化过程中的修饰。我们提出Suv 39 h2，一个组蛋白H3 K9， 甲基转移酶和组蛋白H3 K9去甲基化酶Kdm 3a可以作为发育开关调节， TS细胞干细胞状态和特化滋养层功能的获得。通过染色质修饰 例如由Suv 39 h2和Kdm 3a基因网络工程化的那些基因可以被激活或沉默。在这 本课题的主要目的是：1）研究组蛋白H3 K9甲基化机制对TS细胞的影响 更新和分化; 2）鉴定与动态组蛋白H3 K9甲基化变化相关的基因网络 在TS细胞更新和分化过程中; 3）阐明转录因子和共调节子回路， 影响组蛋白H3 K9甲基化机制。本研究利用体外干细胞模型和体内大鼠模型， 目的：探讨组蛋白H3 K9甲基化在TS细胞状态调控中的作用。拟议研究 提供了一种创新的方法来研究TS细胞的调控，并扩大我们对早期 流产

PROJECT SUMMARY/ABSTRACT (RESEARCH PROJECT III) The establishment of pregnancy requires acquisition of key competencies within the embryo and female reproductive tract. Central to embryo competence is development of the trophoblast lineage, which represents the initial differentiation event during embryogenesis. Trophoblast cells are situated at the embryo-uterine interface and contribute fundamentally to the growth and survival of the embryo in the female reproductive tract. These vital tasks are accomplished through appropriate expansion of trophoblast stem (TS) cells and their accrual of specializations facilitating trophoblast modification of the uterine environment. Disruptions in trophoblast lineage development are associated with implantation failure, recurrent pregnancy loss, and a range of diseases affecting placentation, fetal growth, and postnatal development. Thus it is essential to understand molecular mechanisms underlying the regulation of TS cell renewal and differentiation. Transcriptional and epigenetic regulators control these fundamental processes, which are conserved across species utilizing hemochorial placentation. We have demonstrated the involvement of a defined set of histone modifications in the process of TS cell renewal and differentiation. We propose that Suv39h2, a histone H3K9 methyl transferase, and Kdm3a, a histone H3K9 demethylase, can act as a developmental switches regulating the TS cell stem state and acquisition of specialized trophoblast functions. Through chromatin modifications such as those engineered by Suv39h2 and Kdm3a networks of genes can be activated or silenced. In this project, three aims are proposed: 1) to evaluate the impact of histone H3K9 methylation machinery on TS cell renewal and differentiation; 2) to identify gene networks linked to dynamic histone H3K9 methylation changes during TS cell renewal and differentiation; 3) to elucidate transcription factor and co-regulator circuitry that impacts histone H3K9 methylation machinery. The investigation utilizes in vitro stem cell models and in vivo rat models to explore the role of histone H3K9 methylation in regulating the TS cell state. The proposed research provides an innovative approach to study TS cell regulation and to expand our understanding of early pregnancy loss.